Compounds with sulphonamide group and pharmaceutical compositions containing these compounds

ABSTRACT

The invention relates to compounds which, acting as a prodrug and/or support, enable an active agent to be taken up by the erythrocytes and/or an active agent to bind to the erythrocytes. The uptake of these compounds by and/or the binding thereof to the erythrocytes is made possible by a group of formula —SO2NR1R2, wherein R1 and R2, independently of each other, mean a hydrogen atom, an acyl group, an alkyl group, a cycloalkyl group, an aryl group, a cyano group or a hydroxy group. The inventive prodrugs enable active agents such as endogenic substances, natural substances and synthetic substances with therapeutically useful properties which have a high “first path” effect, to be administered orally effectively or significantly improve the oral activity thereof.

[0001] This invention relates to compounds that as prodrugs and/orvehicles make it possible to take up an active ingredient intoerythrocytes and/or to bind an active ingredient to erythrocytes.

[0002] The purpose of this invention is to make active ingredients, suchas endogenous substances, natural substances and synthetic substanceswith therapeutically valuable properties and with a high “first pass”effect, available orally to a reasonable extent or to improve themdecisively relative to oral activity.

[0003] This purpose is achieved by an-optionally substituted sulfonamidegroup being incorporated in the active ingredient, i.e. as an “anchor,”that makes possible the uptake into erythrocytes or the binding toerythrocytes.

[0004] This means that this invention relates to compounds that asprodrugs and/or vehicles make it possible to take up an activeingredient into erythrocytes and/or to bind an active ingredient toerythrocytes, whereby the uptake of the compounds into erythrocytesand/or the binding of the compounds to erythrocytes is made possible bya group

—SO₂NR¹R²

[0005] whereby R¹ and R², independently of one another, mean a hydrogenatom, an acyl group, an alkyl group, a cycloalkyl group, an aryl group,a cyano group or a hydroxy group.

[0006] One of radicals R¹ and R² preferably means a hydrogen atom; bothradicals R¹ and R² especially preferably mean a hydrogen atom.

[0007] The N-mono-substituted compounds or N,N-disubstituted compoundsof the invention can have one or two N-alkyl, N-alkenyl, N-cycloalkyl,N-acyl or N-aryl substituents, which in each case preferably have up to10 carbon atoms. R¹ and/or R² mean in particular an alkyl or acyl groupwith 1 to 6 carbon atoms. Examples are a methyl, ethyl,. propyl orisopropyl group or the corresponding acyl derivatives. Examples of anaryl group are a phenyl group or a tolyl group. Examples of a cycloalkylgroup are a cyclopentyl group or a cyclohexyl group.

[0008] There are indications that in oral administration, both radicalsR¹ and R², if they are different from a hydrogen atom, are cleaved offand are replaced by a hydrogen atom, so that in this case, not the group—SO₂NR¹R², but rather the group —SO₂NH₂ is provided for the uptake intoerythrocytes or binding to erythrocytes. FIG. 1 is a diagram that showsthe different activity distribution for tritium around ¹⁴C onerythrocytes and plasma after oral administration of17β-hydroxy-estra-1,3,5(10)-trien-3-yl-(N-acetyl)sulfamate (J1045,¹⁴C-labeled acyl substituent and ³H-labeled steroid skeleton). As can beseen from the figure, the ¹⁴C-labeled acyl substituent of the sulfamateradical is no longer present in the-blood after oral administration. Thedata also confirm that substances according to the invention areenriched in the erythrocyte compartment relative to the plasma.

[0009] The sulfonamide group that is preferred according to theinvention can thus also be formed first in the body fromN-monosubstituted or N,N-disubstituted sulfonamide groups, for exampleN-acylsulfonamides.

[0010] According to the invention, a prodrug (pro-pharmaceutical agent)is defined as a pharmaceutical agent that is also largely inactivebiologically and that is reacted into the actual active ingredient onlyonce it enters the body. In addition to the actions of the activeingredient, the prodrug can also have additional pharmacologicalactions. If these actions are predominantly or fully therapy-relevantactions, the compounds according to the invention are to be consideredin boundary cases also as active ingredients and not just as prodrugs(“vehicles”).

[0011] The uptake of compounds into erythrocytes or the binding ofcompounds to erythrocytes is carried out via hemoglobin, membraneproteins and/or carboanhydrase, i.e., carboanhydrase I (hCAI) and II(hCAII).

[0012] A depot of the active ingredient is formed in erythrocytes by theuptake of compounds into erythrocytes and/or by the binding of thecompounds to erythrocytes, whereby an essential portion of the activeingredient in the body is present in erythrocytes.

[0013] According to the invention, the term “depot formation” is definedin that the compound (or the active ingredient) is enriched in theerythrocytes by a factor 10 to 1000, preferably 20 to 1000, especiallypreferably 30 to 1000, above the plasma level, whereby the factor isdetermined after separation from erythrocytes and plasma by centrifugingand determining the concentration of the substance according to theinvention in erythrocytes and plasma. For estradiol sulfamate (J995), itwas found that the above-mentioned factor is 98:2 at any time.

[0014] Basically, the compounds are compounds that exert their action inthe erythrocytes. The compounds and/or the active ingredient containedin the compounds in this case preferably prevent the parasitic attack ofthe erythrocytes that is an essential aspect of the disease, forexample, in malaria.

[0015] The compounds preferably have the following structure:

Active-ingredient-[Spacer]n-SO₂NR¹R²

[0016] whereby n means a number 0 or 1 R¹ and R² have the meaning givenabove, and the active ingredient in its free form has at least onefunctional group, whereby preferably at least one of radicals R¹ and R²means a hydrogen atom and especially preferably both mean a hydrogenatom.

[0017] If the compounds act as a prodrug, the therapeutically desirableaction is obtained by release, especially hydrolytic cleavage, of theactive ingredient that is contained in the product and/or itsmetabolites. For J995, it was found that this compound is stable in theerythrocytes, and the release of the active ingredient from the prodrugis carried out only in the plasma or in tissues.

[0018] If n is 0, the functional group is preferably

[0019] a group —OH, which forms a group —O—SO₂NH₂ with the group—SO₂NH₂,

[0020] a group ═O, which is converted into a group ═N—OH or ═N—NH₂ andforms a group ═N—O—SO₂NH₂ or ═N—NH—SO₂NH₂ with the group —SO₂NH₂,

[0021] a group —NHR, which forms a group —NR—SO₂NH₂ with the group—SO₂NH₂, whereby R is a hydrogen atom or an alkyl group, preferably with1 to 4 carbon atoms, or NR is part of a heterocyclic ring system, as isthe case, for example, in melatonin or some of the cited anti-malariaagents, or

[0022] a group —SH, which forms a group —S—SO₂NH₂ with the group—SO₂NH₂.

[0023] If n is 1, the functional group is preferably a group —COOH or agroup that is derived from this group, such as an ester group, whichtogether with the spacer and with the group —SO₂NH₂ forms a group—C(O)-spacer-SO₂NH₂, whereby the spacer in this case is agroup-A-B-(O)_(s), whereby s is a number 0 or 1, A stands for S, O orNR³, whereby R³ is a hydrogen atom, an alkyl group, preferably with 1 to4 carbon atoms, or an acyl group, preferably with 1 to 4 carbon atoms,and B is selected from an alkylene group, an arylene group, an alkylenearylene group or an alkylene arylenealkylene group, which are optionallysubstituted.

[0024] If n is 1, the functional group is also preferably a group —YH,which together with the spacer and with the group —SO₂NH₂ forms a group—Y-spacer-SO₂NH₂, whereby Y stands for S, O or NR₄, whereby R⁴ is ahydrogen atom, an acyl group, preferably with 1 to 4 carbon atoms, or analkyl group, preferably with 1 to 4 carbon atoms, or NR⁴ is part of aheterocyclic ring system, whereby the spacer is a group

[0025] whereby t and p are a number 0 or 1, and E is selected from analkylene group, an arylene group, an alkylene arylene group or analkylene arylenealkylene group, which optionally are substituted, or,whereby the spacer means a group

[0026] whereby n and q are a number 0 or 1, R⁵ and R⁶, independently ofone another, mean a hydrogen atom or an alkyl group, preferably with 1to 4 carbon atoms, and D means an arylene group, especially a phenylenegroup, or whereby the spacer means a group

[0027] whereby r and v are a number 0 or 1, and m means a number from 1to 15.

[0028] The structure of the compounds according to the invention wasexplained for reasons of simplicity based on the group —SO₂NH₂. What isstated above for the group —SO₂NH₂ correspondingly applies to the group—SO₂NR R².

[0029] The active ingredient can basically be any active ingredient thathas at least one of the above-mentioned functional groups and is bondedby means of the latter, optionally via a spacer, to the group —SO₂NR R².

[0030] The active ingredient is preferably selected from androgens,anabolic agents, antiandrogens, estrogens, gestagens, glucocorticoids,amoebicides, anti-diuretic agents, antigonatropines, ulcer therapeuticagents, neuropharmaceutical agents, dopamine receptor antagonists,dopamine, apomorphine, melatonin and peptides, such as GnRH (gonatropinreleasing hormones) and other hypothalamic, regulatory active peptides.

[0031] The active ingredient is preferably an androgen, such astestosterone, whereby the functional group is the 17-hydroxy group orthe 3-carbonyl group of the androgen.

[0032] The active ingredient is preferably an estrogen, such asestradiol, estriol or estrone, whereby the functional group is a 3-, 16-or 17-hydroxy group or 17-carbonyl group.

[0033] The active ingredient is preferably a gestagen, such asnorethisterone, dienogest, drospirenone or levonorgestrel, whereby thefunctional group is a 17-hydroxy group or a 3-carbonyl group.

[0034] The active ingredient is especially preferably an anti-malariaagent, such as arteether, artemether, artesunate, chloroquine,pamaquine, primaquine, pyrethamine, mefloquine, proguanil, cinchonidine,cinchonine, hydroxychloroquine, pamaquine, primaquine, pyrimethamine aswell as quinine or a quinine derivative, such as quinine-bisulfate,quinine-carbonate, quinine-dihydrobromide, quinine-dihydrochloride,quinine-ethylcarbonate, quinine-formate, quinine-gluconate,quinine-hydroiodide, quinine-hydrochloride, quinine-salicylate orquinine-sulfate.

[0035] The compounds (prodrugs) impart to the pharmaceutical substances,in addition to their pharmodynamic properties, the ability to accumulatein the red blood cells (erythrocytes). This results in the followingtherapy-relevant properties or advantages:

[0036] 1. Endogenous substances, natural substances and syntheticsubstances with therapeutically valuable properties with a high “firstpass” effect are available orally to a reasonable extent only by thedescribed modification or are decisively improved relative to oralactivity. The uptake of the substances according to the invention intothe erythrocytes prevents their extraction from the blood during the(first) passage through the liver and thus their metabolism andexcretion.

[0037] 2. The modification according to the invention results in areduction of undesirable effects of these substances in the liver incomparison to the unsubstituted starting substance.

[0038] 3. The concentration in erythrocytes by a multiple of the plasmaconcentration can be used especially if the action in the erythrocyte isthe purpose of the therapy. This is the case in parasitic attack oferythrocytes, for example in malaria.

[0039] 4. Almost all endogenous hormones, transmitter substances andmany active ingredients are limited in their therapeutic applicabilityby metabolism that occurs too quickly and elimination. The modificationaccording to the invention results in a decisive extension of the dwelltime of the active substance in the organism via a depot that isproduced in the erythrocytes. The occurrence of very high levels in theplasma shortly after the administration is avoided. This is anadvantage, especially in the case of all substances that exert actionsin the central and peripheral nervous system.

[0040] 5. This invention describes, i.a., prodrugs. The prodrugs arebonded to erythrocytes. The therapeutically desired action is carriedout by the (hydrolytic) release of the acid from its prodrug.

[0041] The compounds according to the invention can be used in principlein connection with transcutaneous administration, inhalation orinjection. The therapy-relevant properties or advantages of the prodrugsaccording to the invention are used in particular in oraladministration, however.

[0042] By nature, the success of a pharmacotherapy depends decisively onthe pharmacodynamic and pharmacokinetic properties of the respectivetherapeutic agents. In addition, the form of dispensing thepharmaceutical agent is decisive for the success of the therapy. Thelatter has a decisive influence on the applicability of a principle ofaction by physician or patient and the “compliance” of the patient. Itcan be considered as certain that an oral therapy form ensures a better“compliance” than any other form of administration.

[0043] One reason for the high acceptance of the oral administration isfor one thing the simplicity of the administration and the goodcontrollability of a therapy. Another essential reason for the excellent“compliance” of the oral administration should be related to the factthat we are accustomed to taking food, liquid and stimulants by mouth.Other administration processes can be regarded as traumatic orunnatural, however, and are thus discouraged in terms of longer-lastingforms of therapy.

[0044]FIG. 1 shows the distribution of the total radioactivity of³H/¹⁴C-J 1045 vs. ³H-J 995 after a one-time oral administration.

[0045]FIG. 2 explains the principle according to the invention based onJ995.

[0046]FIG. 3 shows the chemical synthesis of a linkable estradiolsulfamate (J1242) and the immobilization of this ligand.

[0047]FIGS. 4 and 5 show analyses of an affinity-chromatography fractionin Western Blots.

FUNCTIONAL GROUPS

[0048] The functional group can basically be any group with which agroup —SO₂NR R² can be introduced, optionally by means of a spacer.

[0049] As already stated above, the compounds according to the inventionpreferably have the following structure:

Active ingredient-[Spacer]n-SO₂NH₂

[0050] whereby n means a number 0 or 1, and the active ingredient in thefree form has a functional group.

[0051] If n is 0, the functional group is preferably

[0052] a group —OH, which forms a group —O—SO₂NH₂ with the group—SO₂NH₂,

[0053] a group ═O, which is converted into a group ═N—OH or ═N—NH₂ andforms a group ═N—O—SO₂NH₂ or ═N—NH—SO₂NH₂ with the group —SO₂NH₂,

[0054] a group —NHR, which forms a group —NR—SO₂NH₂ with the group—SO₂NH₂, whereby R is a hydrogen atom or an alkyl group, preferably with1 to 4 carbon atoms, or NR is part of a heterocyclic ring system, or

[0055] a group —SH, which forms a group —S—SO₂NH₂ with the group—SO₂NH₂.

[0056] If is 1, the functional group can be a group —COOH (or a groupderived therefrom, such as an ester group), which together with thespacer and with the group —SO₂NH₂ forms a group —C(O)-spacer—SO₂NH₂.

[0057] If n is 1, the functional group in addition can be a group —YH,which together with the spacer and with the group —SO₂NH₂ forms a group—Y-spacer—SO₂NH₂, whereby Y means S, O or NR⁴, whereby R⁴ is a hydrogenatom or an alkyl group, preferably with 1 to 4 carbon atoms, or NR⁴ ispart of a heterocyclic ring system.

[0058] Active Ingredients

[0059] The active ingredient can basically be any active ingredient thathas a functional group and can be bonded via the latter, optionally viaa spacer, to the group —SO₂NR R².

[0060] The principle according to the invention is suitable especiallyfor endogenous substances, natural substances and synthetic substanceswith therapeutically valuable properties that have a high “first pass”effect. The latter are actually available orally to a reasonable extentonly by the described modification or are decisively improved relativeto oral activity.

[0061] In particular, the principle according to the invention for thefollowing active ingredient classes or active ingredients is suitable:

[0062] Hormones that can be described by the skeleton that is citedbelow and have at least one functional group, preferably one of theabove-mentioned functional groups, in the molecule, to which the groupSO₂NR R²

[0063] can be coupled.

[0064] Anabolic agents or androgens that have a group HO— or C═Opreferably in 3- or 17-position, whereby examples of anabolic agents arenandrolone, mentenolone, and trenbolone (functional group: C═O or OH) aswell as prasterone (functional group: C═O or OH) and examples ofandrogens are mesterolone, dehydroepiandrosterone and testosterone(functional group: C═O or OH).

[0065] Antiandrogens, such as Casodex® (functional group: OH) andcyproterone or cyproterone-acetate (functional group: OH, C═O).

[0066] Gestagens that have a group HO— or C═O preferably in 3- or17-position, whereby example are dienogest, levonorgestrel,hydroxyprogesterone, norethisterone as well as gestagens that arederived from ethinylestradiol or 17α-hydroxyprogesterone or19-nortestosterone (functional group: 17-OH, 3-C═O), and drospirenone(functional group: C═O).

[0067] Estrogens that preferably have a 3-, 16- or 17-hydroxy groupand/or 17-carbonyl group as a functional group, such as estradiol,estriol or estrone (functional group: OH group, C═O group).

[0068] Glucocorticoids, such as cortisone, dexamethasone andprednisolone (functional group: OH, C═O).

[0069] Amoebicides, such as metronidazole, chlorotetracycline,oxytetracycline, demecycline, and tetracycline (functional group: OH) aswell as chlorochin (functional group: NH).

[0070] Antidiuretic agents, such as vasopressin, desmopresin,felypressin, lypressin, ornipressin and terlipressin (functional group:NH).

[0071] Antigonadotropins, such as danazol and paroxypropione (functionalgroup: OH).

[0072] Ulcer therapeutic agents, such as the prostaglandin misoprostol(functional group: OH).

[0073] Dopamine receptor agonists, such as dopexamine, lisuride andpergolide (functional group: OH and/or NH) as well as dopamine(functional group: OH).

[0074] Neuropharmaceutical agents and agents against cancer.

[0075] Peptides, such as GnRH and other hypothalamic, regulatory activepeptides.

[0076] Antimalaria agents, such as arteether, artemether, artemisinine,artesunate (functional group: OH, C═O), chloroquine, pamaquine,primaquine, pyrethamine (functional group: NH), mefloquine (functionalgroup: NH, OH), proguanil (functional group: C═NH), cinchonidine,cinchonine (functional group: OH), hydroxychloroquine (functional group:OH, NH), pamaquine, primaquine, pyrimethamine (functional group: NH) aswell as quinine and quinine derivatives, such as quinine-bisulfate,quinine-carbonate, quinine-dihydrobromide, quinine-dihydrochloride,quinine-ethylcarbonate, quinine-formate, quinine-gluconate,quinine-hydroiodide, quinine-hydrochloride, quinine-salicylate andquinine-sulfate (functional group: OH).

[0077] Spacer

[0078] According to the invention, the term “spacer” is defined as acarbon chain and/or one or more aryl groups between the group —SO₂NHRand the functional group of the active ingredient.

[0079] Because of the bio-availability and the transport through themembranes, the compounds according to the invention preferably have amolecular weight below 600.

[0080] If the functional group is a group —COOH, the spacer ispreferably a group-A-B-(O)_(s)—, whereby s is a number 0 or 1, A standsfor S, O or NR , whereby R³ is a hydrogen atom, an alkyl group,preferably with 1 to 4 carbon atoms, or an acyl group, preferably with 1to 4 carbon atoms, and B is selected from an alkylene group, an arylenegroup, an alkylene arylene group or an alkylene arylenealkylene group,which are optionally substituted.

[0081] If the functional group is a group —YH, the spacer is preferablya group

[0082] whereby t and p are a number 0 or 1, and E is selected from analkylene group, an arylene group, an alkylene arylene group or analkylene arylenealkylene group, which optionally are substituted, or agroup

[0083] whereby q and n are a number 0 or 1, R⁵ and R⁶, independently ofone another, mean a hydrogen atom or an alkyl group, preferably with 1to 4 carbon atoms, and D means an arylene group, especially a phenylenegroup, which optionally can be substituted, or a group

[0084] whereby r and v are a number 0 or 1, and m means a number from 1to 15.

[0085] Alkylene group is defined according to the invention as abranched or unbranched alkylene group with 1 (or 2) to 20, preferably 1(or 2) to 10 carbon atoms, which optionally can be substituted. Thesubstituent or substituents can be selected from C₁₋₄-alkyl groups,C₁₋₄-alkoxy groups, C₁₋₄-acyl groups, halogen atoms, such as a fluorine,chlorine,.bromine or iodine atom, a hydroxy group or a carbonyl group.Examples of an alkylene group are methylene, ethylene, propylene,butylene, pentylene, hexylene, heptylene, octylene, nonylene, decyleneand undecylene groups, which can be branched or unbranched andoptionally can be substituted with one or more of the above-mentionedsubstituents.

[0086] The term alkylene group according to the invention also comprisesa branched or unbranched alkenylene group and an alkinylene group with 2(or 3) to 20, preferably 2 (or 3) to 10 carbon atoms, which optionallycan be substituted with the above-mentioned substituents. Examples of analkenylene or alkinylene group are derived from the examples that areprovided above for the alkylene group, whereby one or more double bondsor triple bonds (up to 4) can be present.

[0087] The term alkylene group according to the invention also comprisesa cycloalkylene group with 5 to 20, preferably 5 to 10 carbon atoms,which optionally can be substituted. Examples are a cyclopentylene orcyclohexylene group.

[0088] An arylene group is defined according to the invention as anarylene group with 6 to 20 carbon atoms, which optionally can besubstituted. The substituent or substituents can be selected fromhalogen atoms, such as a fluorine, chlorine, bromine or iodine atom, ahydroxy group, an amino group, a nitro group, a C₁₋₄ alkoxy group, anacyl group, or a C₁₋₄-alkyl group. Examples of an arylene group are aphenylene group, a halophenylene group, a hydroxyphenylene group or anaphthylene group, whereby a phenylene group is preferred.

[0089] An arylene group is also defined according to the invention as aheteroarylene group with 5 to 20 carbon atoms, whereby 1 to 3 carbonatoms can be replaced by a sulfur atom, an oxygen atom or a nitrogenatom. Examples of a heteroarylene group are derived from a pyridine,furan, thiophene, pyrrole, imidazole, pyrazine, pyrimidine or pyridazinering.

[0090] An alkylene arylene group is defined according to the inventionas an unbranched or branched alkylene group with 1 to 14 carbon atoms,which is associated with an arylene group with 6 to 19 carbon atoms. Forboth radicals, the definitions already provided above for the alkylenegroup or arylene group hold true with the exception of the number ofcarbon atoms. Examples of an alkylene arylene group are a benzylidenegroup or a substituted benzylidene group, in which-one or both hydrogenatoms of the methylene group are exchanged for a C₁₋₄-alkyl group.

[0091] An alkylene arylenealkylene group is defined according to theinvention as a branched or unbranched alkylene group with 1 to 13 carbonatoms, which is associated with an arylene group with 6 to 18 carbonatoms, which in turn is associated with an unbranched or branchedalkylene group with 1 to 13 carbon atoms. For both types of groups, thedefinitions already provided above for the alkylene group or arylenegroup hold true with the exception of the number of carbon atoms.Preferred is a group

[0092] whereby f and i are a number 0 or 1,-g and h mean a number from 1to 5, and R⁷ and R⁸, independently of one another, mean a hydrogen atomor a C₁₋₄-alkyl group.

[0093] Examples of an alkyl group with 1 to 4 carbon atoms are a methyl,ethyl, propyl, iso-propyl, butyl- or tert-butyl group.

[0094] Examples of an alkoxy group with 1 to 4 carbon atoms are amethoxy, ethoxy, propoxy, isopropoxy and tert-butyloxy group.

[0095] Examples of a C₁₋₄acyl group are an acetyl group, propionyl groupor butyryl group.

[0096] Halogen atom is defined in this invention as a fluorine,chlorine, bromine or iodine atom.

[0097] Pharmaceutical Compositions

[0098] Subjects of the invention are also pharmaceutical compositionsthat contain at least one compound according to the invention togetherwith pharmaceutically compatible adjuvants and/or vehicles.

[0099] Pharmaceutical agents of this invention are produced withcommonly used solid or liquid vehicles and/or diluents and the adjuvantsthat are generally commonly used according to the desired type ofadministration in a suitable dosage and in a way that is known in theart. In the preferred oral dispensing form, tablets, film tablets,coated tablets, capsules, pills, powders, solutions or suspensions arealso preferably prepared as depot forms.

[0100] Pharmaceutical forms as tablets can be obtained, for example, bymixing active ingredient with known adjuvants, such as dextrose, sugar,sorbitol, mannitol, polyvinyl pyrrolidone, explosives such as cornstarch or alginic acid, binders such as starch or gelatin, lubricantssuch as magnesium stearate or talc. The tablets can also consist ofmultiple layers or can have a break-line.

[0101] In addition, coated tablets can be prepared by coating coresproduced analogously to the tablets with agents that are commonly usedin tablet coatings, for example polyvinyl pyrrolidone or shellac, gumarabic, talc, titanium dioxide or sugar. The shell of the coated tabletin this case can also consist of several layers, whereby, for example,the above-mentioned adjuvants are used.

[0102] Solutions or suspensions with the active ingredient according tothe invention can be mixed with substances such as saccharine, cyclamateor sugar and/or with flavoring substances, such as vanilla or orangeextract, to improve the taste. In addition, they can be mixed withsuspending adjuvants, such as sodium carboxymethyl cellulose, orpreservatives such as p-hydroxybenzoic acid.

[0103] The preparation of capsules can be carried out by mixing apharmaceutical substance with vehicles such as lactose or sorbitol,which then are introduced into the capsules.

[0104] The production of suppositories is preferably carried out bymixing the active ingredient with suitable support materials such asneutral fats or polyethylene glycols or derivatives thereof.

[0105] A high oral bio-availability of the active ingredient is producedfrom the depot effect that allows, on the one hand, very low dosages ofthe sulfamate and, on the other hand, the application at longerintervals.

[0106] This means that the dosages for the compounds according to theinvention, if they are used as a prodrug, can be very much lower in oraladministration than in administration of the active ingredient itselfthat is contained in the prodrug, and the active ingredient can beadministered at longer intervals.

[0107] For J995, it was found, for example, that the individual dosageunit can be. 20-300 μg of estrogen sulfamate for an administrationinterval of 1 to 3 days, 0.5-5.0 mg of estrogen sulfamate for anadministration interval of 5 to 10 days, or 2.0-20 mg of estrogensulfamate for an administration interval of 20 to 40 days.

[0108] The compounds, active ingredients and spacers according to theinvention are commercially available or can be produced according to theprocesses that are known in the literature [see, for example, S. Schwarzet al., Steroids 61 (1996) 710-717; Pharmazie [Pharmaceutics] 30 (1975)17 ff., WO96/05216, WO97/14712, WO93/05064, DE-A-1203042, Appel,Senkpiel, Chem. Ber. 92 (1959) 1102-1104, G. Weiss, G. Schulze, JustusLiebigs Ann. Chem. 729 (1969) 40-51, M. J. Reed et al., Pharm. Sci.(1996) 11-16, U. G. Sahm et al., Pharm. Sci. (1996) 17-20].

[0109] Presentation of the Advantages of the Principle According to theInvention:

[0110] Estrogen sulfamates are prodrugs of estrogens and showpharmacokinetic properties that are different from the estrogens afteroral administration, comparable kinetics that are achieved in the caseof transdermal administration. After oral administration, estradiolsulfamate is resorbed by the gastrointestinal tract and is taken up intoerythrocytes or bonded to erythrocytes. By the uptake into erythrocytesor by the binding to erythrocytes, the extraction of the sulfamate fromthe blood during the (first) liver passage and thus its metabolism andexcretion are prevented, causing the estradiol sulfamate to show, i.a.,a reduced hepatic estrogenicity. The estradiol sulfamate is enriched inthe erythrocytes by a multiple (factor: 98:2) of the plasmaconcentration, whereby a depot of the estradiol sulfamate is producedthat makes possible the slow release of the estradiol sulfamate intoperipheral tissues and target tissues (see FIG. 2). This makes possiblean extension of the dwell time of the estradiol sulfamate in theorganism, and the occurrence of very high levels in the plasma isavoided.

[0111] Characteristic of the estradiol sulfamate are the following:

[0112] (a) Uptake of the prodrug into erythrocytes or binding of theprodrug to erythrocytes and

[0113] (b) Concentration of the prodrug in the erythrocytes by amultiple of the plasma concentration (depot effect).

[0114] (c) Slow release of the active ingredient from the depot.

[0115] The following advantages are produced therefrom:

[0116] Very uniform and prolonged active ingredient level in the bloodbased on the depot effect,

[0117] High oral bio-availability of the active ingredient, which on theone hand allows very low dosages of the sulfamate and, on the otherhand, allows the administration at longer intervals,

[0118] Reduction of the individual variation of blood levels, as well as

[0119] Reduction of the hepatic estrogenic action.

[0120] Identification of the Specific Carrier Protein for EstradiolSulfamate in Erythrocytes

[0121] In FIG. 3, the chemical synthesis of a linkable estradiolsulfamate (J1242) is shown, which is described in S. Schwarz et al.,Steroids 64 (1999) 460-471.

[0122] After the estradiol sulfamate derivative is immobilized in thecolumn material (E-AH-sepharose), proteins of erythrocyte-lysates wereseparated on the column. The protein that is responsible for the bindingof estradiol sulfamate in erythrocytes was adsorbed on the surface ofthe affinity chromatography column. After the protein remaining on thecolumn was washed and eluted with an acetate buffer, the eluate wasanalyzed with use of the “Western Plot Technique” (see FIGS. 4 and 5).

[0123] As a result, it was found that the estradiol sulfamate inerythrocytes binds to the carboanhydrase II (hCA II). The affinitychromatography shows that protein components of the erythrocytes arespecifically bonded, whereby this result does not exclude the binding ofestradiol sulfamate and of substances according to the invention toother proteins in erythrocytes, if the affinity of these proteins toJ1242 lags behind that of hCA II.

1. Compound that as a prodrug and/or vehicle makes it possible to takeup an active ingredient into erythrocytes and/or to bind an activeingredient to erythrocytes, characterized in that the uptake of thecompound into erythrocytes and/or the binding of the compound toerythrocytes is made possible by a group —SO₂NR¹R² whereby R¹ and R²,independently of one another, is a hydrogen atom, an acyl radical, analkyl radical, a cycloalkyl radical, an aryl radical, a cyano group or ahydroxy group:
 2. Compound according to claim 1, whereby the uptake ofthe compound into erythrocytes and/or the binding of the compound toerythrocytes is carried out via hemoglobin, membrane proteins and/orcarboanhydrase.
 3. Compound according to claim 1 and/or 2, whereby adepot of the active ingredient in the erythrocytes is formed by theuptake of the compound into erythrocytes and/or by the binding of thecompound to erythrocytes, whereby an essential part of the activeingredient is present in the body in erythrocytes.
 4. Compound accordingto claim 3, whereby the compound is enriched in the erythrocytes by afactor 10 to 1000 above the plasma level.
 5. Compound according to oneof claims 1 to 4, whereby the compound is a compound that exerts itsaction in the erythrocytes.
 6. Compound according to one of claims 2 to5, wherein the compound is a prodrug that has the following structure:Active ingredient-[Spacer]n-SO₂NR¹R² whereby n means a number 0 or 1, R¹and R² have the meaning that is given in claim 1, and the activeingredient in its free form has a functional group.
 7. Compoundaccording to claim 6, whereby one of radicals R¹ and R² means a hydrogenatom.
 8. Compound according to claim 7, whereby R¹ and R² mean ahydrogen atom.
 9. Compound according to one of claims 6 to 8, wherebythe compound and/or the active ingredient that is contained in thecompound prevents the parasitic attack of the erythrocytes.
 10. Compoundaccording to claim 9, whereby the active ingredient is an anti-malariaagent, such as arteether, artemether, artesunate, chloroquine,pamaquine, primaquine, pyrethamine, mefloquine, proguanil, cinchonidine,cinchonine, hydroxychloroquine, pamaquine, primaquine, pyrimethamine,quinine or a quinine derivative, such as quinine-bisulfate,quinine-carbonate, quinine-dihydrobromide, quinine-dihydro chloride,quinine-ethylcarbonate, quinine-formate, quinine-gluconate,quinine-hydroiodide, quinine-hydrochloride, quinine-salicylate orquinine-sulfate.
 11. Compound according to one of claims 1 to 10,whereby the therapeutically desired action is carried out by release,especially hydrolytic cleavage, of the active ingredient that iscontained in the prodrug and/or its metabolites.
 12. Compound accordingto one of claims 6 to 8, whereby n is 0, and the functional group is agroup —OH, which forms a group —O—SO₂NH₂ with the group —SO₂NH₂; a group═O, which is converted into a group ═N—OH or ═N—NH₂ and forms a group═N—O—SO₂NH₂ or ═N—NH—SO₂NH₂ with the group —SO₂NH₂; a group —NHR, whichforms a group —NR—SO₂NH₂ with the group —SO₂NH₂, whereby R is a hydrogenatom or an alkyl radical or NR is part of a heterocyclic ring system, ora group —SH, which forms a group —S—SO₂NH₂ with the group —SO₂NH₂. 13.Compound according to claim 6, whereby n is 1, and the functional groupis a group —COOH, which together with the spacer and with the group—SO₂NH₂ forms a group —C(O)-spacer-SO₂NH₂.
 14. Compound according toclaim 11, whereby the spacer is a group -A-B-(O)_(s), whereby s is anumber 0 or 1, A stands for S, O or NR³, whereby R³ is a hydrogen atom,an alkyl radical or an acyl radical, and B is selected from an alkylenegroup, an arylene group, an alkylene arylene group or an alkylenearylenealkylene group, which optionally are substituted.
 15. Compoundaccording to claim 8, whereby n is 1, and the functional group is agroup —YH, which together with the spacer and with the group —SO₂NH₂forms a group —Y-spacer-SO₂NH₂, whereby Y stands for S, O or NR ,whereby R⁴ is a hydrogen atom, an alkyl radical or an acyl radical, orNR⁴ is part of a heterocyclic ring system.
 16. Compound according toclaim 15, whereby the spacer is a group

whereby t and p are a number 0 or 1, and E is selected from an alkylenegroup, an arylene group, an alkylene arylene group or an alkylenearylenealkylene group, which optionally are substituted.
 17. Compoundaccording to claim 15, whereby the spacer means a group

whereby q and n are a number 0 or 1, R⁵ and R⁶, independently of oneanother, mean a hydrogen atom or an alkyl radical, and D means anarylene group, especially a phenylene group, which optionally can besubstituted.
 18. Compound according to claim 13, whereby the spacermeans a group

whereby r and v are a number 0 or 1, and m means a number from 1 to 15.19. Compound according to one of claims 16 to 18, whereby the functionalgroup is a group —OH.
 20. Compound according to one of claims 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and/or 20, whereby the activeingredient is selected from androgens, anabolic agents, anti androgens,estrogens, gestagens glucocorticoids, amoebicides; anti-diuretic agents,antigonatropines, ulcer therapeutic agents, neuropharmaceutical agents,dopamine receptor antagonists, dopamine, apomorphine, melatonin andpeptides, such as GnRH, and other hypothalamic, regulatory activepeptides.
 21. Compound according to claim 20, whereby the activeingredient is an androgen, and the functional group is the 17-hydroxygroup or the 3-carbonyl group of the androgen.
 22. Compound according toclaim 21, whereby the androgen is testosterone.
 23. Compound accordingto claim 20, whereby the active ingredient is an estrogen, and thefunctional group is a 3-, 16- or 17-hydroxy group or 17-carbonyl group.24. Compound according to claim 23, whereby the active ingredient isselected from estradiol, estriol or estrone.
 25. Compound according toclaim 20, whereby the active ingredient is a gestagen, and thefunctional group is a 17-hydroxy group or a 3-carbonyl group. 26.Compound according to claim 25, whereby the active ingredient isselected from norethisterone, dienogest, drospirenone or levonorgestrel.